GLOMERULAR UP-REGULATION OF EIIIA AND V120 FIBRONECTIN ISOFORMS IN PROLIFERATIVE IMMUNE-COMPLEX NEPHRITIS

Fibronectins (FNs) comprise a family of adhesive glycoproteins that ar e prominent components of mesangial extracellular matrix and accumulat e during glomerular injury. By alternative splicing of an unique mRNA precursor, various FN isoforms can be originated, in rat, three region s of the molecule are involved: EIIIA, EIIIB and V. Because specific F N isoforms are expressed in embryogenesis and wound healing, condition s characterized by cell migration and adhesion, we examined the patter n of FN isoforms in the mild and severe phases of a progressive immune complex proliferative nephritis in rats. We constructed specific prob es to analyze the splicing pattern of FN pre-mRNAs by ribonuclease pro tection assays. FN mRNAs containing EIIIA, EIIIB and V regions increas ed along the progression of nephritis, though the increment of EIIIB-F N mRNA was modest. However, different regulation of all these isoforms was observed. The percentage of FN mRNA containing the EIIIA exon ver sus total FN increased with thr severity of the disease, while the per centage of FN mRNA containing the EIIIB exon decreased, Relative V-FN mRNA expression versus total FN mRNA increased only in the severe phas e. By means of specific antibodies we also studied the presence of EII IA, EIIIB and V-FN proteins in the kidney, Ln the normal glomerulus, E IIIA-FN protein was barely detectable in the mesangium, increasing in the mild phase of nephritis. In the severe phase of nephritis, increas ed EIIIA-FN was localized in the mesangium, in Bowman's capsule and in crescents. By contrast, EIIIB-FN protein in the glomerulus was absent even in the severe phase, V120-FN protein, an isoform that mediates t he attachment of leukocytes through the VLA-4 integrin, was present in the mesangium and glomerular capillary loops in control animals, and increased in the severe phase of nephritis, coinciding with a strong l eukocyte infiltration. In conclusion, our results show that during imm une glomerular injury there were marked changes in the pattern of FN i soforms expression. Since those isoforms, particularly V120 isoform, a re important in cell adhesion and migration, their up-regulation may f acilitate the recruitment of cells into the injured glomeruli. The blo ckade of the interaction between V120-FN and infiltrating leukocytes m ap represent a new approach to the treatment of nephritis.